This is a competitive renewal for our "Natural history of HPV; infection to neoplasia" grant. The natural history of HPV is most likely influenced by both innate and adaptive mucosal immunity. More specifically, we hypothesize that Tolllike receptors (TLRs) play an important role in cervical innate immunity to HPV through secretions of proinflammatory, chemotactic and anti-viral cytokines. Up-regulated TLR expression will also result in activation of dendritic cells and T cells that in turn will promote a Thl like response through secretion of several cytokines and consequently, the induction of a successful cell mediated immune (CMI) response. We propose to: 1) examine, in cervical cell samples, the association among TRL expression,TRL-associated cytokines that mediate innate immunity ( IFN alpha, TNF, IL-6 and IL-8) and clearance of incident HPV infection; 2) examine, in cervical cell samples, the association among TRL expression, TRL-associated cytokines that induce and mediate adaptive immunity (IFN-gamma, ILs- 12, 23, and 27) and HPV clearance; and 3) examine the association among TLR induced Th-1 responses measured in cervical cell samples, HPV specific CMI responses detected in peripheral blood (PB) and HPV clearance. Adolescent and young women who were a) entered into the cohort during the initial 1990-1995 period and have continued to be followed and b) entered into the cohort during the last recruitment wave (2000-2005) will be asked to continue follow-up for an additional five years (2005-2010). These women will have been well characterized at the time of the initiation of this study with HPV at their entry visit and 4-month interval sampling for HPV DNA, cytology, bacterial vaginosis, colpophotographs (assessment of cervical maturation), C. trachomatis and N. gonorrohea testing, cervical cell cytokines by RT-PCR (IFN-gamma, ILs 4,10 and 12) and PB CMI for HPV 16 positive women. Women will be continued to be characterized for the above at the same intervals through-out the follow-up. Measures of innate and adaptive immunity (TLRs, ILs-6, 8, 5, 13, 23, and 27, TNF, IFN alpha) by RT PCR using cervical cells and by Luminex technology using cervical mucous will be added to the same 4 month interval testing as HPV DNA, cytology and other cervical cytokines described. Women positive for HPV 16 will get additional blood for CMI using IFN-gamma EliSpot technique for detection of anti-E6 and E7 responses. We acknowledge that this design simplifies the pleiotropic nature of cytokines. However, we feel that this model reflects plausible mechanisms involved in HPV control and is feasible to test in our cohort. Information garnered from this type of study will be critical in developing vaccine strategies and therapies as well as illuminating immune responses developed in the mucosal epithelium.